Journal of Biological Chemistry
Volume 276, Issue 40, 5 October 2001, Pages 37373-37378
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MECHANISMS OF SIGNAL TRANSDUCTION
Multiple Levels of Control Regulate the Yeast cAMP-response Element-binding Protein Repressor Sko1p in Response to Stress*

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The Sko1p transcriptional repressor regulates a subset of osmoinducible stress defense genes inSaccharomyces cerevisiae by binding to cAMP-responsive elements. We have reported previously that in response to stress Sko1p is phosphorylated by the stress-activated Hog1p mitogen-activated protein kinase, which disrupts its interaction with the Ssn6p·Tup1p corepressor. Here we report that other mechanisms are essential for the regulation of the Sko1p repressor activity upon stress. The nuclear localization of Sko1p depends on the stress-inhibited protein kinase A (PKA). Sko1p is localized in the nucleus of unstressed cells, and it redistributes to the cytosol upon severe salt stress (1 mNaCl). Yeast mutants with low PKA activity localize Sko1p to the cytoplasm in the absence of stress and exhibit deregulated expression of cAMP-responsive element-regulated genes. The central part (315) of Sko1p, containing the PKA phosphorylation sites and the basic domain-leucine zipper domain, is essential for its nuclear localization. Salt-induced export of Sko1p from the nucleus is independent of Hog1p and of the Bcy1p regulatory subunit of PKA. Furthermore, phosphorylation by PKA slightly enhanced DNA binding affinity of Sko1p in vitro, whereas Sko1p dimerizationin vivo is not regulated by stress. Sko1p repressor activity is associated to its binding to the Ssn6p·Tup1p complex. Interestingly, the Sko1p NH2 terminus (1), containing the Hog1p phosphorylation sites, associates in vivo with Tup1p in the absence of Ssn6p, suggesting that Sko1p represses gene transcription by interacting directly with the Tup1p subunit of the Ssn6p·Tup1p complex.

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Published, JBC Papers in Press, August 10, 2001, DOI 10.1074/jbc.M105755200

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Present address: Dept. Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.

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This work was supported in part by a predoctoral grant from the Spanish government (to A. P.-A.), by European Training and Mobility of Researchers Grant ERB-FMRX-CT96-0007 (to M. P.), and by Grant PM99-0028 from the Ministerio de Ciencia y Tecnologia (to F. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.